Mutations in the rhodopsin gene are associated with and are the most common cause of RP. More than 70 mutations, mostly single amino acid changes have been identified in rhodopsin and these have been observed in all the three, intradiscal, transmembrane and cytoplasmic domains. Work on the in vivo folding pathway of rhodopsin from this laboratory has demonstrated that a variety of site-specific mutations in the P23H, G188R in the intradiscal domain as well as the mutation L125R in the transmembrane helix C, which have been identified in RP, have been shown to cause misfolding of the corresponding opsins. The questions to be asked in the present research proposal are the following: (1) how many of the known RP mutations in rhodopsin actually cause partial or total misfolding and what are their overall consequences in visual transduction; (2) what is the precise chemical nature of the abnormal covalent linkage, a disulfide bond, that characterizes misfolding in RP mutants; and (3) can rearrangement of the wrong disulfide bond to the normal disulfide bond, that characterizes the correctly folded opsin, be achieved in vitro with possible significance in vivo.